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1. Introduction

Fibromyalgia (FM) is characterized by the presence of widespread musculoskeletal pain and tenderness accompanied by fatigue, cognitive/emotional, and sleep-related symptoms, occurring without any other medical explanation.77 Besides its high prevalence and clinical relevance,79 there is an inherent problem associated with the diagnosis of FM, in that there is an absence of laboratory findings or well-characterized pathology that is sensitive and specific for the disorder. The existence of FM as a clinical diagnosis has been therefore historically questioned.79 The past 2 decades of research, however, have provided consistent evidence to suggest abnormal nervous system findings in patients with FM.14 Of note, neuroimaging studies have shown augmented responses to a variety of painful stimuli in FM,15,25,56 and altered brain structure, metabolic activity, and resting state functional connectivity in regions that are consistently involved in processing pain.23,28,34,36,38,44,50,57,58,60,61

In addition to pain-related changes, patients with FM show reduced tolerance (augmented unpleasantness) to nonpainful sensory stimulation (visual, auditory, olfactory, and tactile), along with abnormal brain processing of nonpainful sensory stimuli.11,21,30,42,74 Our group42,58 and others31,46,53 have reported evidence suggesting that the brain systems involved in the primary cortical processing of nonpainful sensory signals and their integration may play an important role in FM pain. These studies suggest that pain in FM may be associated with (1) hyperexcitability of the nociceptive system, ie, increased transmission,52,64,69 central amplification,15,25,56 and/or reduced inhibitory control mechanisms35,37 and (2) reduced opponent nonnociceptive sensory processing.31,42,46,53,58 Despite these brain and behavioral findings, there remains a critical gap between characterizing abnormalities in FM at a group level and identifying neurophysiological markers diagnostic of FM at an individual patient level.

Here, we use a multisensory approach to identify a brain signature sensitive to FM status (vs healthy) at the individual-person level. Notably, we do not imply that the signature should differentiate FM from other chronic pain conditions with a sensitization component. We include tests of both mechanical pain and nonpainful sensory brain responses to (1) characterize the sensory processing alterations that are distinctive of FM at the central level and (2) address how such characteristic pathophysiological features relate to patients' core symptoms. As a first approach to assess alterations in central pain processing, we applied the neurologic pain signature (NPS), a multivariate brain activation pattern that was previously validated to be sensitive and specific to predict experimental pain perception at the individual-person level.70 The NPS accurately predicts experimental pain perception but does not respond to other unpleasant, highly arousing emotional experiences.70 Augmented expression of the NPS in FM would indicate enhanced pain-specific cerebral processing in patients. In addition, we applied cross-validated machine learning algorithms to differentiate patients with FM from healthy participants based on their brain responses to (1) pressure pain and (2) combined nonpainful visual, auditory, and tactile motor stimulation. Finally, we combined pain and multisensorybrain measures to obtain a cross-validated signature for FM status.

2. Materials and methods

2.1. Ethics statement

This study was conducted according to the principles expressed in the Declaration of Helsinki and was approved by the Ethics and Institutional Review Board of the Autonomous University of Barcelona (reference number SAF2010-19434). All patients and healthy participants provided written informed consent to participate in the study.

2.2. Subjects

Seventy-two subjects participated, including 37 female patients with FM (1990 American College of Rheumatology criteria for FM)78 and 35 female matched healthy controls (Table 1). Patients and healthy subjects were matched for age, education status, and handedness (all right handed, Table 1). The patients were consecutively recruited during clinical follow-up in the rheumatology service (CIMA, Barcelona) to provide a homogeneous sample with severe and persistent FM symptoms. Vision and hearing were normal upon neurological examination for all patients and healthy participants.

We administered the following scales in a visit before the magnetic resonance imaging (MRI) appointment: Fibromyalgia Impact Questionnaire (FIQ); the 36-Item Short-Form Health Survey, General Perception of Health; the Hospital Anxiety and Depression Scale (HADS).

Patients were allowed to continue with their stable medical treatment, as listed in Table 1, but were asked to refrain from taking occasional rescue analgesic drugs (ie, nonsteroidal anti-inflammatory drugs, paracetamol, and tramadol) 72 hours before scanning session.

Control subjects with relevant medical and neurological disorders, any form of chronic or acute pain, substance abuse, or history of psychiatric illness were not considered for inclusion. Contraindication to MRI including pregnancy was a general exclusion criterion for both groups.

Clinical pain in deep tissue was assessed using a 101-point verbal scale. A score of 0 expressed no pain and a score of 100 the most intense pain imaginable, perceived in the body as a whole, or in most of its extension, rather than referring to any focal tenderness. Patients were asked to report spontaneous pain approximately 1 hour before the scanning session (Table 1). All healthy participants rated “0” for this measure.

2.3.1. Multisensory task

A block-design functional MRI (fMRI) paradigm was used, with alternating 30-second periods of rest (no stimulation) and activation (concurrent visual, auditory, and tactile-motor stimulation), completing a total of 4 rest–stimulation cycles.42 A subset of these data (from 25 controls and 35 patients) was used in a previous publication by our group.42 The multisensory stimuli consisted of the simultaneous presentation of visual (3 Hz, equivalent to 6 color reversals per second) full-field flashing checkerboard composed of a grid of black and white alternating squares (80 ± 10 lux) and auditory stimulation (series of 15 tones of frequencies comprised in the range of 233.1-1318.5 Hz, presented at a temporal frequency of 3 Hz, with an intensity of 75 ± 5 dB) and a finger-opposition task during which subjects were instructed to touch the tip of their right thumb with the other fingers (from index to little finger).42 In our multisensory assessment, we were interested in a more naturalistic presentation of sensory stimuli (and motor response) that are usually combined in daily life rather than in modality-specific alterations. As a first approach, this approach allowed us to maximize signal power and challenge both sensory and motor systems efficiently.

Pressure stimulation tasks involved a block design fMRI paradigm consisting of 3 conditions per stimulation cycle repeated 5 times. Each cycle began with a rest condition with pseudorandom duration (range: 20-32 seconds), followed by a brief auditory stimulus (600-millisecond tone), followed by a 6-second anticipatory period, and then a 10-second pressure pain period. Each subject was asked to rate pain intensity and unpleasantness immediately after the end of the fMRI scanning sequence (run) using a numerical rating scale (NRS) ranging from 0 (not at all painful/unpleasant) to 100 (worst pain imaginable/most unpleasant imaginable). All participants completed a low-pressure pain task first, with pressure set at 4.5 kg/cm2. Approximately 10 minutes later, 28 healthy participants (out of 35) completed a second, high-pressure pain task, with stimulus intensity individualized based on the calibration session to reliably provoke severe but tolerable pain (5.90 ± 0.62 kg/cm2), comparable to the experience of patients with FM at 4.5 kg/cm2.

As in previous studies,25,41,56pressure pain stimuli were delivered using a hydraulic device capable of transmitting controlled pressure to 1-cm2 surface placed on the subjects' right thumbnail. In a calibration session, each subject was trained to report pain intensity and unpleasantness to different pressure stimuli ranging from 2 to 9 kg/cm2 (or up to tolerance threshold) using the NRS described above. A stimulus of 4.5 kg/cm2 was selected to reliably provoke intense pain (above 60 in the NRS but tolerable) in the patient group. This stimulus is only slightly more intense than what was used to determine tender points during clinical assessment in patients (4 kg/cm2). The 10-second 4.5 kg/cm2 was able to evoke, during the calibration assessment, a mean pain intensity of 73.15 ± 19.76 points in the patient group and a 36.47 ± 20.38 points in the healthy control group (between-group effect: t = 7.75, P < 0.0005). For healthy participants, we also determined the minimum pressure intensity that was required during the calibration session to provoke severe (above 60 in the NRS) but tolerable pain (5.90 ± 0.62 kg/cm2).

To address the potential effects of head motion on the FM-status prediction results, we computed a single motion index per subject for each fMRI task (see full description of the method in Ref. 57; see also Ref. 55). Briefly, we computed a measure for mean interframe motion due to translation (x, y, z), mIMtr, and a measure for mean interframe motion due to rotation (pitch, yaw, roll), mIMrot. Although mIMtr is a distance, mIMrot is an angle. The combined measurement was based on an average of both

, where r is the approximate average distance of all brain voxels to the rotation principal axis. The multiplicative factor r is necessary to transform the angle mIMrot to its corresponding distance arc. Following previous authors, we set r = 50 mm.55 Specific details about the computation of mIMtr and mIMrot are provided in Ref. 57; Supplementary Information file (available online at http://links.lww.com/PAIN/A340). We did not observe between-group differences in motion during the multisensory paradigm (t = −0.28, P = 0.78). However, for the pressure pain task, significant differences were observed in TR-by-TR head motion between patients with FM and healthy participants (patients > controls, t = 2.49, P = 0.02) (also between healthy subjects at the high and low-pressure intensities, t = 2.38, P = 0.02), whereas no differences emerged between patients and healthy participants when pain was matched (t = 0.27, P = 0.79). Importantly, the magnitude of the between-group difference in head motion was minimal (95% confidence interval for the head motion difference between patients and healthy participants: 0.01-0.16 mm). To account for the potential influence of head motion in the prediction model of FM status (see below, logistic multiple regression), we added the single subject measures of head motion for each task (pain and multisensory, for the sake of completeness) as independent variables in the model and verified that neither contributed significant variance to explaining the FM status (multisensory task: t = −0.84, P = 0.40; pain task: t = 0.20, P = 0.84).

To test whether motion parameters (during the pain task) were sufficiently informative to correctly classify patients from healthy participants, we used support vector machines (SVMs) with 6 motion regressors per subject as the classification features and the subjects' category (patient vs healthy participant) as the outcome. The results were not significant (cross-validated accuracy: 60% ± 5.7% [SE], P = 0.10). We also checked and confirmed that the time course of the “nociception-positive NPS” response (see below) on a TR-by-TR basis was not correlated with motion parameter estimates, for any regressor for any subject (all P values > 0.1).

We used a conventional general lineal model approach as implemented in SPM8 software to estimate brain responses to (1) multisensory stimulation and (2) pressure stimulation for each subject.

For the multisensory task, a primary task regressor was created by convolving the sensory stimulation blocks with a canonical hemodynamic response function. The “off” (rest) condition served as an implicit task baseline. Parameter estimates were calculated at each voxel using the general linear model. A high-pass filter was used to remove low-frequency signal fluctuations (1/128 Hz). (Multisensory stimulation − baseline) contrast images for each participant were calculated.

For the pressure stimulation task, signal response was modeled using separate regressors for the anticipatory and the pain periods, with a hemodynamic delay of 4 seconds. In 3 previous studies using similar procedures,22,41,56 we systematically observed that the duration of brain responses to 10-second pressure stimuli of similar intensities extends to 16 seconds (average response duration across pain processing regions),41 which is consistent with observations by different research groups.13,47,70 To account for this, pain-related activation was modeled using a pain condition of 16-second duration. A high-pass filter was used to remove low-frequency signal fluctuations (1/128 Hz). In agreement with our previous work,42,56,58,70 we did not model autocorrelations. Modeling autocorrelations has the potential disadvantage of producing biased parameter estimates when the autoregressive (AR) model assumptions are violated, which can result in reduced efficiency.20,80 Of note, models that do not consider autocorrelation have shown to generate unbiased parameter estimates (beta values, which we use here for classification purposes), even if the data are autocorrelated51,80 (see also Supplementary Figure 1, available online at http://links.lww.com/PAIN/A340). (Pressure stimulation − baseline) contrast images for each participant were calculated.

We studied brain response alterations during pain processing in patients with FM using 2 complementary approaches: (1) As a first test of pain-related brain responses, we applied the NPS brain signature,70 a multivariate fMRI-based brain pattern that was validated to specifically predict experimental pain (and not other unpleasant/arousing emotional experiences) in humans. The goal of this approach was to use a defined marker or process that has been well characterized in healthy individuals to test for abnormalities in the patient population. An advantage is that the NPS was trained to track pain intensity in a fine-grained way across multiple levels of stimulus intensity and was tested for specificity to pain and generalizability across a number of independent studies. (2) Because the NPS may not be sufficient to capture all pain-related differences between patients and controls, a second approach was to train a classifier optimized to discriminate patients with FM from controls. This pattern identifies pain-related signals that may be missed by the NPS. This second approach was also applied to the multisensory task (see below).

2.4.4. Computing Neurologic Pain Signature responses

We computed for each subject (patient with FM or healthy participant) a single scalar value representing their expression of the NPS pattern in response to pressure pain (using the contrast [pressure stimulation − baseline] images, as detailed below).

For this analysis, we separated NPS regions likely to be related to nociceptive pain (associated with pain-evoked activation in the NPS) from those that play other modulatory roles (associated with pain-evoked deactivation in the NPS). In most of the regions in the NPS, pain is associated with increased overall activity. Such regions include the major targets of ascending nociceptive afferents, including the thalamus, primary and secondary somatosensory regions (SI/SII), posterior, mid and anterior insula and adjacent opercula, midbrain, dorsal anterior cingulate cortex (ACC), inferior frontal gyrus and amygdala (Supplementary Table 1, available online at http://links.lww.com/PAIN/A340, and Fig. 1). We refer to pattern responses in this set of regions as the “nociception-positive NPS” (NPSp). In a subset of other medial regions, including the perigenual ACC (pgACC) and the posterior cingulate (PCC)/precuneus/paracentral lobule, pain was associated with deactivation in the original NPS pattern. These regions are not strongly linked to nociception and are not direct targets of nociceptive afferents, rather they have been associated with a variety of affective, autonomic, social, self-referential, and decision-making functions.62 We refer to responses in this set of regions as the “nociception-negative NPS” (NPSn) and analyze this pattern separately from the NPSp due to its differential functional characteristics and considering the particular role of these regions, mostly the pgACC, in chronic pain. Of note, the local pattern of voxel weights is exactly the same as in the original NPS within the 2 NPS components (NPSp and NPSn). Supplementary Text 1 provides a detailed description of the rational for computing NPSp and NPSn and the procedure used to characterize them (available online at http://links.lww.com/PAIN/A340).

We performed 2 analyses using linear SVMs to discriminate patients with FM and controls based on whole-brain activation patterns. The first analysis used activation patterns during painful pressure at 4.5 kg/cm2pressure stimulation (FM-pain) and the second analysis used activations during non-painful multisensory stimulation (multisensory). The SVM was implemented in the Spider Toolbox (http://people.kyb.tuebingen.mpg.de/spider). It identifies a hyperplane (direction in multidimensional voxel space) that separates the 2 groups. Distances from the hyperplane are related to the likelihood a participant belongs to the patient vs control class and were used in the logistic regression analysis below.

The FM-pain classifier was based on the (pressure stimulation − baseline) contrast, and the multisensory classifier was based on the (multisensory stimulation − baseline) contrast. In each analysis, we used leave-2-subject-out cross-validation, which ensured that the patterns we identified were always tested on new, out-of-sample individuals (see Supplementary Information, available online at http://links.lww.com/PAIN/A340). Accuracy (sensitivity and specificity) was based on the cross-validation, and the final weight map was based on the full sample and was thresholded using a bootstrap test (q < 0.05 false discovery rate (FDR)-corrected; for a detailed description of the SVM analysis and the bootstrap test, see Supplementary Text 2, available online at http://links.lww.com/PAIN/A340).

We used logistic regression to combine results from the 3 fMRI-based classifiers (NPS, FM-pain, and multisensory) into a single signature of FM status. The predictors in the regression were: (1) the NPSp response, (2) the NPSn response, (3) the cross-validated FM-pain signature response (distance from the hyperplane), and (4) the cross-validated multisensory signature response.

Logistic regression results were used to calculate sensitivity, specificity, and the area under the receiver operating characteristic curve. We assessed these values for each fMRI-based classifier (NPSp, FM-pain, and multisensory) independently and for the combined model.

2.4.8. Multivariate brain pattern responses and medication status

To examine the relationship between medication status and brain pattern responses, we performed a series of 2-sample t tests to compare between-group differences in pattern response between medicated and nonmedicated patients.

2.4.9. Multivariate brain pattern responses and clinical severity

We also tested whether the multivariate fMRI patterns used to classify FM status were correlated with clinical symptom severity. We performed linear regression (stepwise procedure in SPSS), including the 4 brain-derived (cross-validated) pattern response values as predictors (NPSp, NPSn, FM-pain, and multisensory) and each of the clinical measures as the dependent variable in 1 of 3 regression models (clinical pain, FIQ, and HADS depression scores). We included a fourth predictor representing the presence or absence of anxiolytic or antidepressant medication in each model, considering the significant correlation between NPS responses and antidepressant and anxiolytic medication status (further described in the Results section). For completeness, we also assessed zero-order Pearson correlations between brain measures and clinical symptom severity in patients with FM.

We also examined local signature responses in each contiguous region of the NPSp (Fig. 1C and Supplementary Table 1; available online at http://links.lww.com/PAIN/A340). Comparisons between patients with FM and healthy participants showed significantly greater NPSp responses to low-pressure intensity in patients with FM in all regions tested, with one exception (the inferior frontal gyrus). When subjective pain was matched (high pressure in healthy participants vs low pressure in patients with FM), local pattern responses were virtually identical for all regions.

Importantly, after controlling for clinical severity (including clinical pain, HADS, and FIQ scores as covariates), the relationship between anxiolytic and antidepressant use and both NPSp and NPSn responses became nonsignificant (all P > 0.1). These findings suggest that the observed relationship between medication use and brain measures may reflect common influences of symptom severity on both measures; that is, greater symptom severity is associated with both increased medication use and larger NPS responses.

4. Discussion

Diagnosing FM based on objective brain measures is important for several reasons. The status of FM as a disorder with objective physiological dysfunction has been questioned, in part because it is unclear that central23–25,28,32–34,36,39,42,49,50,56,58 and peripheral changes52,64,69 are sufficient to diagnose FM and explain symptoms. Objective brain-based signatures can reveal patterns of neurophysiological alterations characteristic of FM (vs healthy), potentially establishing a specific neurological component to the disorder.

Here, we identify a set of 3 brain patterns based on fMRI responses to pressure pain and nonpainful multisensory stimulation. These patterns, taken together, discriminate FM from matched healthy controls with 92% sensitivity and 94% specificity. Although we take this as a provisional “signature” for FM, we do not imply that these patterns are unique to FM or that they differentiate it from other conditions. Multifocal pain and widespread mechanical hypersensitivity are common features of multiple chronic pain conditions.54,75 Given the overlap in symptoms and comorbidities across disorders,54,75,76 which clinical categories are respected at the neurophysiological level and which clinical features are most likely represented in a continuum, still remain open, empirical questions. Exploratory analyses suggested that the 3 component patterns are correlated with clinical symptoms. Individual patients with FM may vary in the expression of the different brain patterns we identified, which may lead to the characterization of new FM subtypes.

These results show that fMRI may serve as a useful component of multimodal FM assessments. Previously, heart rate variability40 and performance in specific fitness tests3 have shown moderate-to-strong separation of patients and healthy participants. Although these measures are useful and are easy to deploy, they are not suitable for addressing the neurophysiological mechanisms of FM. Previous attempts have established neurophysiological differences in pain-related processing in patients with FM15,24,25,56 but have not yet successfully discriminated patients from healthy participants at the individual-person level.67 A recently published study based on brain anatomy findings shows ability to discriminate patients with FM with from 53% to 76% accuracy in different data sets.61 Our ability to classify with 93% accuracy in the present study relies strongly on the joint consideration of responses to nociceptive and nonpainful multisensory stimuli, following previous work.42,56,58

4.1. Brain features diagnostic of fibromyalgia

4.1.1. Combined pain-multisensory neural classifier

Our study provides 3 distinct neural targets for objective patient characterization. A model combining: (1) enhanced responses in the NPSp, a pain-specific brain network, (2) a pattern of brain responses to painful pressure (FM-pain pattern), and (3) a pattern of extranociceptive multisensory responses, differentiated patients with FM vs healthy participants with 93% cross-validated accuracy. The 3 effects are theoretically significant. Stronger NPSp responses mediated mechanical hyperalgesia in FM and were associated with a trend to greater depression; stronger FM-pain and multisensory responses were associated with greater clinical pain. Thus, the combined model is most likely to be useful for clinical and translational purposes, although either feature might also be used alone. Although the NPSn was not significant in the final model, NPSn responses may nonetheless be important for assessing and understanding functional aspects of FM.

4.1.2. Pain-related patterns

The NPSp pattern showed an augmented response in FM when the stimulus intensity was matched, but not when subjective pain was matched. It was a significant mediator of mechanical hypersensitivity in patients. Thus, NPSp responses are enhanced in patients in proportion to their augmented subjective experience of pressure-induced pain and are consistent with previous evidence supporting peripheral (Refs. 52,64,69) and central (Refs. 10,45,58,66) sensitization in FM. The current study cannot determine whether this enhancement reflects a change in the gain of the NPSp per unit stimulus intensity or simply reflects enhanced afferent input. Future studies could begin to disentangle these alternatives by testing multiple stimulus intensities in both patients and controls.

Rather than being limited to regions associated most strongly with emotional or evaluative aspects of pain (eg, anterior insula, ACC, lateral PFC), our findings showed a distributed enhancement of nociceptive processing affecting all major NPSp regions. In agreement with previous observations25,56 and considering the validation properties of the NPS, the results provide evidence of augmented pain-specific responses in FM, consistent with peripheral/central sensitization.

NPSp responses were predictive of experimental pain but not ongoing clinical pain intensity, consistent with work showing that medial prefrontal-striatal systems rather than classic nociceptive systems are correlated with chronic low back pain.6

The NPSn pattern includes patterns within medial regions in which greater deactivation was previously associated with increased pain.70 In this study, however, increased pain was associated with greater activations in healthy participants (specifically for the PCC/precuneus cluster) and patients with FM (for both the PCC/precuneus and the pgACC clusters). The pgACC showed increased activation specifically for patients with FM, in agreement with previous findings showing that chronic pain patients do not deactivate pgACC/medial PFC and/or surrounding regions of the “default mode” network as strongly as controls do (and sometimes show activation).2,5,6,12,27,63,72 Conversely, the PCC/precuneus may activate in response to pressure-evoked pain in both healthy4,16,43,65 and patient populations.27,48,59,65 The value of “default mode” network regions as predictors of pain may therefore vary across pain modalities and pain patient groups. We discuss the issue in detail in Supplementary Text 3 (available online at http://links.lww.com/PAIN/A340).

The FM-pain pattern complements the NPS results by showing that FM was best characterized by concurrently augmented pain-evoked activation in regions that show an important role in sensory integration (anterior SII extending to middle insula) and “default mode” regions and reduced activation of the dorsolateral PFC, a region commonly found to play a role in pain and emotion regulation.71,73 This pattern, which was (together with the multisensory) predictive of clinical pain in patients, also emphasizes the importance of some key regions that are not part of the NPS (and are important for self-related, motivational, and emotional regulation) as targets for future study in FM.

Supplementary analyses of medication use indicated that it was not sufficient to explain the relationship between the status of patients with FM and alterations in brain activity (Supplementary Text 4, available online at http://links.lww.com/PAIN/A340).

The multisensory pattern is the feature that most strongly discriminates patients with FM from healthy participants, with and without controlling for NPS and FM-pain responses, and contributes to predict clinical pain. Central processing of nonpainful sensory signals may be of particular importance in maintaining clinical pain in FM, in agreement with previous work.29,42,58 Consistently, Harte et al.29 very recently showed that fMRI data during a visual task could discriminate patients with FM vs healthy controls with 82% accuracy. The multisensory pattern shows early sensory cortical processing attenuation, which is consistent with reduced processing of fine sensory/discriminative properties of stimulus,1,18,46,53 accompanied by amplification of sensory integration (in agreement with Ref. 29) and self-referential aspects of the response, including potential threat of harm.17

The FM-pain pattern could accurately classify patients vs controls using multisensorybrain responses and vice versa, which may reflect a more global brain reorganization in FM that may be detected across a range of experimental conditions. Our study and others show overlapping brain functional alterations during rest and task performance in FM and other chronic pain conditions involving sensory integration (eg, Refs. 19,36,42,58), salience (Refs. 33,42,50,58,68), and default-mode network regions (eg, Refs. 6–8,49,50,58).

Overall, we have found an augmented NPSp response that is consistent with enhanced nociceptive processing, and partly mediates augmented mechanical pain, and, more broadly, evidence for central nervous system alteration in brain processing of sensory stimuli that go beyond nociception, consistent with a central nervous system pathophysiological component in FM.

Several limitations and future directions remain to be addressed in future studies. First, replication of these results with fully independent validation samples is a next step toward translational utility. The validation process is a long, multistudy, and multipublication effort.9,26 Second, false-negative cases, ie, patients who are erroneously classified as healthy controls using these brain measures, are always a possibility. Importantly, these brain patterns may not capture other sensory/affective/cognitive processes that may also be altered in patients with FM. Third, the brain pattern–symptom severity correlations that we present are preliminary and need replication in multiple samples. Fourth, further studies are needed to test whether our findings generalize to other chronic pain populations or are specific to FM. Last, all participants included in the study were females and therefore the findings cannot be generalized to the population of men with FM, for which future generalization and validation studies are warranted.

Overall, an important open question concerns the extent to which FM and other chronic pain disorders are pathophysiologically distinct or may share certain brain features independent of primary etiology. Testing the generalizability of the brain patterns we identify here may advance our understanding regarding the common and independent central pathophysiology of distinct chronic pain conditions across domains of sensory processing. Thus, the current approach may help in identifying pain endophenotypes across a spectrum of chronic pain conditions and in providing objective guidance for therapeutic interventions on an individualized basis.

Conflict of interest statement

The authors declare no conflict of interests.

This work was supported in part by grant R01DA035484 (T.D.W.) and by grant SAF2010-19434 (Ministry of Science and Innovation of Spain, J.D.). M. López-Solà's work was supported by a Beatriu de Pinos-A Postdoctoral Fellowship (2010_BP_A_00136) from the Government of Catalunya.

The Agency of University and Research Funding Management of the Catalonia Government participated in the context of Research Groups SGR 2009/718, 1435 and 1450. MATLAB code implementing the analyses presented here is available at wagerlab.colorado.edu.

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